Normalization of Obesity-Associated Insulin Resistance through Immunotherapy: CD4+ T Cells Control Glucose Homeostasis
By S. Winer, Yin Chan, G. Paltser, Dorothy Truong, Hubert Tsui, J. Bahrami, R. Dorfman, Yongqian Wang, J. Zieleński, F. Mastronardi and 5 more. Nature Medicine, 2009
788 citations recorded by the source corpus.
Obesity and its associated metabolic syndromes represent a growing global challenge, yet mechanistic understanding of this pathology and current therapeutics are unsatisfactory. We discovered that CD4+ T lymphocytes, resident in visceral adipose tissue (VAT), control insulin resistance in mice with diet-induced obesity (DIO). Analyses of human tissue suggest that a similar process may also occur in humans. DIO VAT-associated T cells show severely biased T cell receptor Vα repertoires, suggesting antigen-specific expansion. CD4+ T lymphocyte control of glucose homeostasis is compromised in DIO progression, when VAT accumulates pathogenic interferon-γ (IFN-γ)-secreting T helper type 1 (TH1) cells, overwhelming static numbers of TH2 (CD4+GATA-binding protein-3 (GATA-3)+) and regulatory forkhead box P3 (Foxp3)+ T cells. CD4+ (but not CD8+) T cell transfer into lymphocyte-free Rag1-null DIO mice reversed weight gain and insulin resistance, predominantly through TH2 cells. In obese WT and ob/ob (leptin-deficient) mice, brief treatment with CD3-specific antibody or its F(ab′)2 fragment, reduces the predominance of TH1 cells over Foxp3+ cells, reversing insulin resistance for months, despite continuation of a high-fat diet. Our data suggest that the progression of obesity-associated metabolic abnormalities is under the pathophysiological control of CD4+ T cells. The eventual failure of this control, with expanding adiposity and pathogenic VAT T cells, can successfully be reversed by immunotherapy.
Subfields: Epidemiology, Genetics, Immunology
View Paper: https://www.semanticscholar.org/paper/53edcc540582590d884c729b32a9bf6b218d6b18
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Citations in the corpus
- B Lymphocytes Promote Insulin Resistance through Modulation of T Lymphocytes and Production of Pathogenic IgG Antibody (2011, background): “T cells are also major participants in VAT inflammation, with proinflammatory CD8 + T cells and interferon-γ (IFN-γ)-producing CD4 + T cells contributing to inflammation, glucose intolerance and insulin resistance in DIO mic”
- Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease (2010, neutral): “…(and recruitment of professional immune cells to this site) (Alexaki et al., 2009; Feuerer et al., 2009; Liu et al., 2009; Nishimura et al., 2009; Winer et al., 2009), whether triggered metabolically or through injury or death of adipocytes, can be linked to a diverse set of stress responses…”
- Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. (2014, background): “Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and anti-inflammatory (T helper 2 and regulatory T lymphocytes) CD4 cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39–41].”
- Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes (2020, background): “In contrast, the number of CD3+CD4+ Th2 cells is declined in obese AT (Winer et al., 2009; Lee et al., 2018).”